The present invention relates to certain new compounds believed to be useful in the treatment of glaucoma. The compounds are structurally related to ethacrynic acid, which is a compound having diuretic and anti-allergic properties and which has been described as being useful in the treatment of glaucoma.
Glaucoma is a progressive disease which leads to optic nerve damage, and, ultimately, partial or total loss of vision. The causes of this disease have been the subject of extensive studies for many years, but are still not fully understood. The principal symptom of the disease is an elevated pressure within the eye caused by excess intraocular fluid (i.e., "aqueous humor").
The reasons why the excess fluid accumulates are not fully understood. It is known that the elevated intraocular pressure ("IOP") can be at least partially controlled by administering drugs which affect either the production of aqueous humor within the eye or the flow of aqueous humor out of the eye. The glaucoma therapies currently available primarily involve the use of drugs which act to reduce production of aqueous humor by the ciliary body of the eye. These therapies have been generally effective in the majority of patients. However, it is not always possible to control chronic elevations of IOP by reducing the amount of aqueous humor production, particularly in cases where obstructed outflow of aqueous humor is contributing to the excess of aqueous humor and consequent elevation of IOP. Moreover, the reduction of aqueous humor production creates a risk that the avascular tissues of the eye, particularly the lens and the cornea, will be damaged due to an inadequate supply of nutrients and/or hydration caused by the reduced production of aqueous humor. The possible use of agents which increase the outflow of aqueous humor to control IOP has therefore been a topic of great interest to scientists engaged in glaucoma research.
The use of ethacrynic acid ("ECA") to increase the outflow of aqueous humor has been reported in the literature. This use is described in U.S. Pat No. 4,757,089 issued to David L. Epstein. The Epstein '089 patent describes a method of increasing aqueous humor outflow by topically administering ECA, or analogs of ECA which are capable of reacting with sulfhydryl groups in the trabecular meshwork of the eye. Epstein postulates that chemical modification of cellular sulfhydryl groups by ECA or ECA analogs alters the egress of aqueous humor from the trabecular meshwork.
Unfortunately, there are serious limitations on the topical ophthalmic use of ECA due to its poor penetration of the cornea. ECA, a carboxylic acid with a pK of 3.5, exists essentially exclusively (greater than 99.9%) in its ionic form, the carboxylate anion, at physiological pH (7.4). Therefore, in spite of the favorable lipophilicity of the neutral species (calculated log P of 3.19), the species present at physiologic pH, the ionic form, has an extremely unfavorable lipophilicity (experimental log P is -1.15); therefore, the ability of ECA or analogs to penetrate lipophilic corneal membranes at physiological pH is extremely poor. The limited ocular penetration of these acidic compounds severely limits the practical value of ECA in glaucoma therapy, because if the drug can not effectively penetrate the cornea, a therapeutic level of the drug at the postulated site of action (i.e., the trabecular meshwork) will not be achieved.